Information about ageing & neurodegenerative diseases
What are neurodegenerative diseases (ND)?
“Neuro” refers to matters of the nervous system which comprises:
- The central nervous system (CNS), including the brain and the spinal cord.
- The peripheral nerves connecting the CNS to all parts of the body. Motor nerves control muscles and organs, and sensory nerves receive information about the environment (our senses) and the state of our body.
- A key element of the nervous system are its nerve cells (neurons) which wire our body through their up-to-a-meter long cable-like extension (called axons) which conduct and pass on information in form of nerve impulses (action potentials) within the nervous system (the upper neuron in the animation connects the brain to the spinal cord) or to other body parts, including muscles and glands (the lower neuron stimulates a muscle instructing it to bend the arm). Nerve impulses are passed on to other cells at highly specialised cell connections called synapses (see the layman’s guide to synapses as well as the following YouTube movie).
- “Degeneration” is when something breaks down (i.e. the opposite of generation). Neurodegeneration therefore means the breaking down of parts of the nervous system, usually through loss of nerve cells and/or nerves (in the second animation, the distal axon of the lower neuron has degenerated, shown as stippled line). As the animation illustrates, such loss of elements may cause gaps in our hard-wired neuronal networks and therefore loss of cognitive and physical faculties. This is best illustrated by spinal cord injury where nerve connections in the spinal cord are irreversibly interrupted leading to paralysis of the body beneath this point.
- You’ve probably heard that every time you bash your head in an accident, you lose a huge number of nerve cells. Furthermore, neurodegeneration is a slow, natural process during healthy ageing. and we gradually lose about 50% of our nerve connections towards high age. But don’t worry! The nervous system is constructed to have many back-ups, and it can compensate for loss of elements through re-wiring processes, referred to as neuroplasticity. Therefore, a surprisingly large number of neurons can be lost before any physical or mental changes can be noticed.
However, the process of nervous system decay is accelerated by neurodegenerative diseases (NDs), such as in dementia (e.g. Alzheimer’s disease, Frontotemporal dementia), Parkinson’s disease or motorneuron disease. If suffering from mild ND, the loss of neural elements exceeds our body’s capacity to compensate, and symptoms are more likely to manifest when you get older. Therefore, ageing is the biggest risk factor for many NDs.
- With increasing life expectancy in the Western world, NDs pose therefore a substantial burden on our societies, especially since they cause enormous personal hardship and monetary cost. In Europe, the cost of brain disorders to societies was estimated as being €798 billion (£400 billion) in 2010 (Gustavsson et al., 2011, Eur Neuropsychopharmacol 21, 718ff. – LINK).
- In severe forms of ND, decay sets in so fast that symptoms can manifest already at young age. A famous case is Prof Stephen Hawking who suffers from an early-onset, slow-progressing form of Motorneuron Disease, called Amyotrophic Lateral Sclerosis (ALS). Prof. Hawking’s disease history was described in the recent film “The theory of everything“.
- In some families, ND occurs more often than in the normal population (familial cases of ND). This suggests a genetic predisposition. Thus, genes make proteins which are essential for cell functions, and many NDs are caused by proteins turned dysfunctional, or forming pathological aggregates, eventually leading to cellular malfunctions or decay of neurons. Using human genetics with focus on familial forms of ND is therefore a good starting point. Many genes linking to ND have been identified, and their study teaches us about the causes and mechanisms of the respective disease.
- However, many cases of ND show no familial inheritance, and so they are considered multifactorial – this means that many causes may contribute to them. These cases are far more difficult to study and understand, since even environmental factors may contribute.
- To date, we still know far too little about the causes of NDs and we mostly do not understand why nerve cells die. Therefore, further research into NDs is pivotal, and all possible lines of investigation need to be employed. One very effective strategy for fundamental research into NDs is the use of the fruit fly Drosophila, and this if further explained on the page “4. ND in Drosophila“.
Some examples of neurodegenerative diseases
Alzheimer’s Disease Fact File
- The most common form of dementia and age-related neurodegenerative disease. More common in women than men.
- First described in 1907 by Alois Alzheimer.
- Symptoms include: memory loss, cognitive impairments, psychosis, paranoia, personality changes.
- Changes in the brain: narrowed gyri, widened sulci, enlarged ventricles, decrease in size. This happens as the result of the vast numbers of degenerating neurons.
- Pathological characteristics: swollen axons, specific intracellular protein aggregates (called neurofibrillary tangles) and extracellular protein aggregates (called amyloid plaques).
- Risk factors for late onset: age, lifestyle factors such as obesity
- Risk factors for early onset: family history of the disease with a few genes having been identified, which can be looked up in the “Online Mendelian Inheritance in Man” (OMIM) data base here.
- Example: Presenilin is responsible for cleaving (cutting) Amyloid Precursor Protein (APP). Mutations in the genes for Presenilin or for APP itself may cause abnormal APP cleavage, and its product is then more likely to aggregate and form amyloid plaques.
- For more information on Alzheimer’s disease, please visit the dedicated pages from the NHS and the Alzheimer’s Society.
Parkinson’s Disease Fact File
- The second most common age-related neurodegenerative disease; more common in men than women.
- Symptoms include: tremor, akinesia, bradykinesia, reduced facial expressions.
- Changes in the brain: loss of dopaminergic neurones in the striatum responsible for generating movement.
- Pathological characteristics: specific intracellular protein aggregates called Lewy bodies, damage of mitochondria (the cell’s power station).
- Risk factors: head trauma, age, exposure to substances such as certain pesticides, and family history of the disease. A few genes have been identified, which can be looked up on OMIM.
- Examples: PINK-1 and parkin work together to ensure that mitochondria function correctly. If the gene for either of them is mutated, then oxidative stress occurs and the toxic products can cause the neurons to die, resulting in Parkinson’s disease.
- Alpha-synuclein can build up to form Lewy bodies, which are seen in several neurodegenerative diseases, including Parkinson’s. Some alpha-synuclein gene mutations make this more likely and, hence, are involved in some familial cases of the disease.
- For more information on Parkinson’s disease, please visit the dedicated pages from the NHS and Parkinson’s UK.
Motor Neuron Disease Fact File
- Also known as: Amyotrophic Lateral Sclerosis (ALS), Lou Gehrig’s disease.
- Uncommon, with around 6 cases per 100,000 people. More common in men than women.
- Symptoms include: muscle weakness, leading to paralysis.
- Motor neurons are responsible for sending signals to the muscles. In motor neuron disease, primarily these neurons die.
- Possible reasons for motor neuron death: inflammation, excitotoxicity (death induced by hyperactivity), protein misfolding, affected transport of materials in neurons.
- Risk factors: age, family history of the disease with a few genes having been identified, which can be looked up here.
- Example: The SOD1 gene has been identified as the cause of between 15% and 20% of all cases of motor neuron disease. SOD1 affects axonal transport within neurons, which subsequently has detrimental effects on the mitochondria, as well as other aspects of the cell.
- For more information on motor neuron disease, please visit the dedicated pages from the NHS and the Motor Neuron Disease Association.
Trinucleotide Repeat Disorders (TRD) Fact File
- Caused by codon repeats which build up and affect protein interactions. These repeat expansions occur because of a mutation in the DNA which changes how the DNA is read.
- The disease class of TRDs includes Frontotemporal Dementia, Huntington’s Disease, multiple variants of Spinocerebellar ataxia, and Kennedy’s disease, a type of motor neuron disease.
- Usually begin in middle age or later.
- Risk factors: family history of the disease with a few genes having been identified, which can be looked up for Huntington’s Disease here and Frontotemporal Dementia here.
- A prominent example for Huntington’s Disease: mutations in the huntingtin gene cause trinucleotide repeat expansions in its DNA; degeneration occurs mostly in the striatum, and symptoms include personality changes, physical and cognitive deficits, and chorea.
- A prominent example for Frontotemporal Dementia is often caused by repeat expansions resulting from a mutation on chromosome 9. Degeneration occurs mostly in the frontal and temporal lobes, and symptoms include personality changes, apathy, and language difficulties.
- For more information on Huntington’s disease, please visit the dedicated pages from the NHS.
- For more information on frontotemporal dementia, please visit the dedicated page from the NHS and information on the Alzheimer’s Society website.